E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1.

TBK1 is essential for interferon-ß (IFN-ß) production and innate antiviral immunity. Here we identified the T cell anergy-related E3 ubiquitin ligase RNF128 as a positive regulator of TBK1 activation. RNF128 directly interacted with TBK1 through its protease-associated (PA) domain and catalyzed the K63-linked polyubiquitination of TBK1, which led to TBK1 activation, IRF3 activation and IFN-ß production. Deficiency of RNF128 expression attenuated IRF3 activation, IFN-ß production and innate antiviral immune responses to RNA and DNA viruses, in vitro and in vivo. Our study identified RNF128 as an E3 ligase for K63-linked ubiquitination and activation of TBK1 and delineated a previously unrecognized function for RNF128.

Multiplex chromatin interactions with single-molecule precision.

The genomes of multicellular organisms are extensively folded into 3D chromosome territories within the nucleus1. Advanced 3D genome-mapping methods that combine proximity ligation and high-throughput sequencing (such as chromosome conformation capture, Hi-C)2, and chromatin immunoprecipitation techniques (such as chromatin interaction analysis by paired-end tag sequencing, ChIA-PET)3, have revealed topologically associating domains4 with frequent chromatin contacts, and have identified chromatin loops mediated by specific protein factors for insulation and regulation of transcription5-7. However, these methods rely on pairwise proximity ligation and reflect population-level views, and thus cannot reveal the detailed nature of chromatin interactions. Although single-cell Hi-C8 potentially overcomes this issue, this method may be limited by the sparsity of data that is inherent to current single-cell assays. Recent advances in microfluidics have opened opportunities for droplet-based genomic analysis9 but this approach has not yet been adapted for chromatin interaction analysis. Here we describe a strategy for multiplex chromatin-interaction analysis via droplet-based and barcode-linked sequencing, which we name ChIA-Drop. We demonstrate the robustness of ChIA-Drop in capturing complex chromatin interactions with single-molecule precision, which has not been possible using methods based on population-level pairwise contacts. By applying ChIA-Drop to Drosophila cells, we show that chromatin topological structures predominantly consist of multiplex chromatin interactions with high heterogeneity; ChIA-Drop also reveals promoter-centred multivalent interactions, which provide topological insights into transcription.

Mechanistic Understanding of Dexamethasone-Mediated Protection against Remdesivir-Induced Hepatotoxicity.

Remdesivir (RDV), a broad-spectrum antiviral agent, is often used together with dexamethasone (DEX) for hospitalized COVID-19 patients requiring respiratory support. Potential hepatic adverse drug reaction is a safety concern associated with the use of RDV. We previously reported that DEX cotreatment effectively mitigates RDV-induced hepatotoxicity and reduces elevated serum alanine aminotransferase and aspartate aminotransferase levels in cultured human primary hepatocytes (HPH) and hospitalized COVID-19 patients, respectively. Yet, the precise mechanism behind this protective drug-drug interaction remains largely unknown. Here, we show that through the activation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling, RDV induces apoptosis (cleavage of caspases 8, 9, and 3), autophagy (increased autophagosome and LC3-II), and mitochondrial damages (decreased membrane potential, respiration, ATP levels, and increased expression of Bax and the released cytosolic cytochrome C) in HPH. Importantly, cotreatment with DEX partially reversed RDV-induced apoptosis, autophagy, and cell death. Mechanistically, DEX deactivates/dephosphorylates p38, JNK, and ERK1/2 signaling by enhancing the expression of dual specificity protein phosphatase 1 (DUSP1), a mitogen-activated protein kinase (MAPK) phosphatase, in a glucocorticoid receptor (GR)-dependent manner. Knockdown of GR in HPH attenuates DEX-mediated DUSP1 induction, MAPK dephosphorylation, as well as protection against RDV-induced hepatotoxicity. Collectively, our findings suggest a molecular mechanism by which DEX modulates the GR-DUSP1-MAPK regulatory axis to alleviate the adverse actions of RDV in the liver. SIGNIFICANCE STATEMENT: The research uncovers the molecular mechanisms by which dexamethasone safeguards against remdesivir-associated liver damage in the context of COVID-19 treatment.

Circulating small extracellular vesicle-based miRNA classifier for follicular thyroid carcinoma: a diagnostic study.

BACKGROUND: The diagnosis of follicular thyroid carcinoma (FTC) prior to surgery remains a major challenge in the clinic. METHODS: This multicentre diagnostic study involved 41 and 150 age- and sex-matched patients in the training cohort and validation cohort, respectively. The diagnostic properties of circulating small extracellular vesicle (sEV)-associated and cell-free RNAs were compared by RNA sequencing in the training cohort. Subsequently, using a quantitative real-time polymerase chain reaction (qRT‒PCR) assay, high-quality candidates were identified to construct an RNA classifier for FTC and verified in the validation cohort. The parallel expression, stability and influence of the RNA classifier on surgical strategy were also investigated. RESULTS: The diagnostic properties of sEV long RNAs, cell-free long RNAs and sEV microRNAs (miRNAs) were comparable and superior to those of cell-free miRNAs in RNA sequencing. Given the clinical application, the circulating sEV miRNA (CirsEV-miR) classifier was developed from five miRNAs based on qRT‒PCR data, which could well identify FTC patients (area under curve [AUC] of 0.924 in the training cohort and 0.844 in the multicentre validation cohort). Further tests revealed that the CirsEV-miR score was significantly correlated with the tumour burden, and the levels of sEV miRNAs were also higher in sEVs from the FTC cell line, organoid and tissue. Additionally, circulating sEV miRNAs remained constant after different treatments, and the addition of the CirsEV-miR classifier as a biomarker improves the current surgical strategy. CONCLUSIONS: The CirsEV-miR classifier could serve as a noninvasive, convenient, specific and stable auxiliary test to help diagnose FTC following ultrasonography.

Ethnicity-specific blood pressure thresholds based on cardiovascular and renal complications: a prospective study in the UK Biobank.

BACKGROUND: The appropriateness of hypertension thresholds for triggering action to prevent cardiovascular and renal complications among non-White populations in the UK is subject to question. Our objective was to establish ethnicity-specific systolic blood pressure (SBP) cutoffs for ethnic minority populations and assess the efficacy of these ethnicity-specific cutoffs in predicting adverse outcomes. METHODS: We analyzed data from UK Biobank, which included 444,418 participants from White, South Asian, Black Caribbean, and Black African populations with no history of cardiorenal complications. We fitted Poisson regression models with continuous SBP and ethnic groups, using Whites as the referent category, for the composite outcome of atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. We determined ethnicity-specific thresholds equivalent to the risks observed in Whites at SBP levels of 120, 130, and 140 mm Hg. We adjusted models for clinical characteristics, sociodemographic factors, and behavioral factors. The performance of ethnicity-specific thresholds for predicting adverse outcomes and associated population-attributable fraction (PAF) was assessed in ethnic minority groups. RESULTS: After a median follow-up of 12.5 years (interquartile range, 11.7-13.2), 32,662 (7.4%) participants had incident composite outcomes. At any given SBP, the predicted incidence rate of the composite outcome was the highest for South Asians, followed by White, Black Caribbean, and Black African. For an equivalent risk of outcomes observed in the White population at an SBP level of 140 mm Hg, the SBP threshold was lower for South Asians (123 mm Hg) and higher for Black Caribbean (156 mm Hg) and Black African (165 mm Hg). Furthermore, hypertension defined by ethnicity-specific thresholds was a stronger predictor and resulted in a larger PAF for composite outcomes in South Asians (21.5% [95% CI, 2.4,36.9] vs. 11.3% [95% CI, 2.6,19.1]) and Black Africans (7.1% [95% CI, 0.2,14.0] vs. 5.7 [95% CI, -16.2,23.5]) compared to hypertension defined by guideline-recommended thresholds. CONCLUSIONS: Guideline-recommended blood pressure thresholds may overestimate risks for the Black population and underestimate risks for South Asians. Using ethnicity-specific SBP thresholds may improve risk estimation and optimize hypertension management toward the goal of eliminating ethnic disparities in cardiorenal complications.

Sarcopenic obesity is part of obesity paradox in dementia development: evidence from a population-based cohort study.

BACKGROUND: Sarcopenic obesity, a clinical and functional condition characterized by the coexistence of obesity and sarcopenia, has not been investigated in relation to dementia risk and its onset. METHODS: We included 208,867 participants from UK biobank, who aged 60 to 69 years at baseline. Dementia diagnoses were identified using hospital records and death register data. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models to evaluate the associations of obesity, sarcopenia, and sarcopenic obesity with dementia risk, stratified by sex. Stratified analyses were performed across dementia-related polygenic risk score (PRS). Restricted mean survival time models were established to estimate the difference and 95%CIs of dementia onset across different status. Additionally, linear regression models were employed to estimate associations of different status with brain imaging parameters. The mediation effects of chronic diseases were also examined. RESULTS: Obese women with high PRS had a decreased risk (HR = 0.855 [0.761-0.961]), but obese men with low PRS had an increased risk (HR = 1.223 [1.045-1.431]). Additionally, sarcopenia was associated with elevated dementia risk (HRwomen = 1.323 [1.064-1.644]; HRmen = 2.144 [1.753-2.621]) in those with low PRS. Among those with high PRS, however, the association was only significant in early-life (HRwomen = 1.679 [1.355-2.081]; HRmen = 2.069 [1.656-2.585]). Of note, sarcopenic obesity was associated with higher dementia risk (HRwomen = 1.424 [1.227-1.653]; HRmen = 1.989 [1.702-2.323]), and results remained similar stratified by PRS. Considering dementia onset, obesity was associated with dementia by 1.114 years delayed in women, however, 0.170 years advanced in men. Sarcopenia (women: 0.080 years; men: 0.192 years) and sarcopenic obesity (women: 0.109 years; men: 0.511 years) respectively advanced dementia onset. Obesity, sarcopenia, and sarcopenic obesity were respectively related to alterations in different brain regions. Association between sarcopenic obesity and dementia was mediated by chronic diseases. CONCLUSIONS: Sarcopenic obesity and sarcopenia were respectively associated with increased dementia risk and advanced dementia onset to vary degree. The role of obesity in dementia may differ by sex and genetic background.

Thermal Property of Fullerene Fibers: One-Dimensional Material with Exceptional Thermal Performance.

The recent groundbreaking achievement in the synthesis of large-sized single crystal C60 monolayer, which is covalently bonded in a plane using C60 as building blocks. The asymmetric lattice structure endows it with anisotropic phonon modes and conductivity. If these C60 are arranged in form of 1D fiber, the improved manipulation of phonon conduction along the fiber axis could be anticipated. Here, thermal properties of C60-fiber, including thermal transfer along the C60-fiber axis and across the interlayer interface are investigated using molecular dynamic simulations. Taking advantage of the distinctively hollow spherical structure of C60 building blocks, the spherical structure deformation and encapsulation induced thermal reduction can be up to 56% and 80%, respectively. By applying external electronic fields in H2O@C60 model, its thermal conductivity decreases up to 60%, which realizes the contactless thermal regulation. ln particular, the thermal rectification phenomenon is discovered by inserting atoms/molecules in C60 with a rational designed mass-gradient, and its maximum thermal rectification factor is predicted to ≈45%. These investigations aim to achieve effective regulation of the thermal conductivity of C60-fibers. This work showcases the potential of C60-fiber in the realms of thermal management and thermal sensing, paving the way to C60-based functional materials.

Maintaining the 2D Structure of MXene via Self-Assembled Monolayers for Efficient Lubrication in High Humidity.

MXene is considered as a promising solid lubricant due to facile shearing ability and tuneable surface chemistry. However, it faces challenges in high-humidity environments where excessive water molecules can significantly impact its 2D structure, thus deteriorating its lubricating properties. In this work, the self-assembled monolayers are formed on MXene by surface chlorination (MXene-Cl) and fluorination (MXene-F), and their friction behaviors in high/low humidity are investigated. The results indicate that MXene-F and MXene-Cl can maintain a relatively constant friction coefficient (CoF) (MXene-F ∼0.76, MXene-Cl ∼0.48) under both high (75%) and low (25%)-relative humidity (RH) environments. Meanwhile, the MXene-F and MXene-Cl display a lower CoF than the pristine MXene (MXene CoF∼1.18) in high humidity. The above phenomena are mainly attributed to the preservation of its 2D layered structure, the increased layer spacing, and superficial partial oxidation for SAMs-functionalized MXene under high humidity during friction. Interestingly, MXene-Cl with moderate water resistance has a lower CoF than that of MXene-F with complete water resistance. The nanostructured water adsorption capacity and larger interlayer spacing of MXene-Cl make it exhibit a lower CoF compared to MXene-F. The findings of this study offer valuable guidance for tailoring MXene by surface chemical functionalization as an efficient solid lubricant in high humidity.

Interferon-γ+ Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.

The immune mechanism underlying hepatitis B surface antigen (HBsAg) loss, particularly type I inflammatory response, during pegylated interferon-α (PEG-IFN) therapy remains unclear. In this study, we aimed to elucidate such immune mechanisms. Overall, 82 patients with chronic hepatitis B (CHB), including 41 with HBsAg loss (cured group) and 41 uncured patients, received nucleos(t)ide analogue and PEG-IFN treatments. Blood samples from all patients, liver tissues from 14 patients with CHB, and hepatic perfusate from 8 liver donors were collected for immune analysis. Jurkat, THP-1 and HepG2.2.15 cell lines were used in cell experiments. The proportion of IFN-γ+ Th1 cells was higher in the cured group than in the uncured group, which was linearly correlated with HBsAg decline and alanine aminotransferase (ALT) levels during treatment. However, CD8+ T cells were weakly associated with HBsAg loss. Serum and intrahepatic levels of Th1 cell-associated chemokines (C-X-C motif chemokine ligand [CXCL] 9, CXCL10, CXCL11, IFN-γ) were significantly lower in the cured patients than in patients with a higher HBsAg quantification during therapy. Serum from cured patients induced more M1 (CD68+CD86+ macrophage) cells than that from uncured patients. Patients with chronic HBV infection had significantly lower proportions of CD86+ M1 and CD206+ M2 macrophages in their livers than healthy controls. M1 polarization of intrahepatic Kupffer cells promoted HBsAg loss by upregulating the effector function of tissue-resident memory T cells with increased ALT levels. IFN-γ+ Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.

Functional, structural, and molecular characterizations of the leukemogenic driver MEF2D-HNRNPUL1 fusion.

Recurrent MEF2D fusions with poor prognosis have been identified in B-cell precursor ALL (BCP-ALL). The molecular mechanisms underlying the pathogenic function of MEF2D fusions are poorly understood. Here, we show that MEF2D-HNRNPUL1 (MH) knock-in mice developed a progressive disease from impaired B-cell development at the pre-pro-B stage to pre-leukemia over 10 to 12 months. When cooperating with NRASG12D, MH drove an outbreak of BCP-ALL, with a more aggressive phenotype than the NRASG12D-induced leukemia. RNA-sequencing identified key networks involved in disease mechanisms. In chromatin immunoprecipitation-sequencing experiments, MH acquired increased chromatin-binding ability, mostly through MEF2D-responsive element (MRE) motifs in target genes, compared with wild-type MEF2D. Using X-ray crystallography, the MEF2D-MRE complex was characterized in atomic resolution, whereas disrupting the MH-DNA interaction alleviated the aberrant target gene expression and the B-cell differentiation arrest. The C-terminal moiety (HNRNPUL1 part) of MH was proven to contribute to the fusion protein's trans-regulatory activity, cofactor recruitment, and homodimerization. Furthermore, targeting MH-driven transactivation of the HDAC family by using the histone deacetylase inhibitor panobinostat in combination with chemotherapy improved the overall survival of MH/NRASG12D BCP-ALL mice. Altogether, these results not only highlight MH as an important driver in leukemogenesis but also provoke targeted intervention against BCP-ALL with MEF2D fusions.

Mesenchymal Stem Cells Promote Polarization of M2 Macrophages in Mice with Acute-On-Chronic Liver Failure via Mertk/JAK1/STAT6 Signaling.

Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.

ELAVL4 promotes the tumorigenesis of small cell lung cancer by stabilizing LncRNA LYPLAL1-DT and enhancing profilin 2 activation.

Small cell lung cancer (SCLC) is one of the most malignant tumors that has an extremely poor prognosis. RNA-binding protein (RBP) and long noncoding RNA (lncRNA) have been shown to be key regulators during tumorigenesis as well as lung tumor progression. However, the role of RBP ELAVL4 and lncRNA LYPLAL1-DT in SCLC remains unclear. In this study, we verified that lncRNA LYPLAL1-DT acts as an SCLC oncogenic lncRNA and was confirmed in vitro and in vivo. Mechanistically, LYPLAL1-DT negatively regulates the expression of miR-204-5p, leading to the upregulation of PFN2, thus, promoting SCLC cell proliferation, migration, and invasion. ELAVL4 has been shown to enhance the stability of LYPLAL1-DT and PFN2 mRNA. Our study reveals a regulatory pathway, where ELAVL4 stabilizes PFN2 and LYPLAL1-DT with the latter further increasing PFN2 expression by blocking the action of miR-204-5p. Upregulated PFN2 ultimately promotes tumorigenesis and invasion in SCLC. These findings provide novel prognostic indicators as well as promising new therapeutic targets for SCLC.

Development and validation of a novel home-made bench-top training model for retrograde intrarenal surgery.

PURPOSE: To develop and validate a low-cost homemade bench-top training model to facilitate retrograde intrarenal surgery (RIRS) training. METHODS: The RIRS training model (G-Model) was developed using a surgical glove and a recycled ureter access sheath. Fifteen participants including 10 residents and 5 urologists were enrolled. Designed training curriculum for residents was carried out. Face validity, content validity, construct validity and criterion validity evaluation of the G-Model were carried out. RESULTS: The global score of face and content validity was 4.15 ± 0.53 and 4.65 ± 0.29, respectively. For construct validity, the overall modified global rating scale (mGRS) score was significantly improved [12.5 (5.25) vs. 24.0 (5.25), p = 0.004], and the total task time was significantly shortened (39.5 ± 4.48 min vs. 24.1 ± 3.81 min, p < 0.001) within residents after G-Model training. The baseline mGRS score and total task time of residents were poorer than those of urologists [12.5 (5.25) vs. 32.0 (1.00), p < 0.001; 39.5 ± 4.48 min vs. 16.0 ± 1.58 min, p < 0.001]. Spearman correlation analysis revealed strong correlations between residents' G-Model and real patient performance. CONCLUSION: The current study presented a valid low-cost easily accessible RIRS bench-top training model which could facilitate skill acquisition and translate to real-life scenario.

Prediction of Transcription Factor Binding Sites on Cell-Free DNA Based on Deep Learning.

Transcription factors (TFs) are important regulatory elements for vital cellular activities, and the identification of transcription factor binding sites (TFBS) can help to explore gene regulatory mechanisms. Research studies have proved that cfDNA (cell-free DNA) shows relatively higher coverage at TFBS due to the protection by TF from degradation by nucleases and short fragments of cfDNA are enriched in TFBS. However, there are still great difficulties in the noninvasive identification of TFBSs from experimental techniques. In this study, we propose a deep learning-based approach that can noninvasively predict TFBSs of cfDNA by learning sequence information from known TFBSs through convolutional neural networks. Under the addition of long short-term memory, our model achieved an area under the curve of 84%. Based on this model to predict cfDNA, we found consistent motifs in cfDNA fragments and lower coverage occurred upstream and downstream of these cfDNA fragments, which is consistent with a previous study. We also found that the binding sites of the same TF differ in different cell lines. TF-specific target genes were detected from cfDNA and were enriched in cancer-related pathways. In summary, our method of locating TFBSs from plasma has the potential to reflect the intrinsic regulatory mechanism from a noninvasive perspective and provide technical guidance for dynamic monitoring of disease in clinical practice.

Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

Performance Evaluation of Newly-Developed Tumor Markers Assay Kit Based on Flow Fluorescence Assay.

BACKGROUND: The purpose of this study is to evaluate the performance of recently developed tumor marker clinical kits in China, with the aim of encouraging local medical technology innovation and thus narrowing the research and development gap with foreign kits. METHODS: The newly established reagent kits were analyzed on the TESMI F3999-Luminex200 flow lattice instrument to verify precision, sensitivity (blank limit), linearity, anti-interference ability, carry-over contamination rate, hook effect, and reference interval verification. Additionally, the newly established reagent kits were compared to other commercially available detection kits (reference reagent kits) to analyze the correlation between the two types of kits. RESULTS: The intra-assay and inter-assay precision had coefficients of variations (CVs) less than 3.50% and 6.91%, respectively. The tumor marker blank limits were lower than the manufacturer's statement. The newly established reagent kits demonstrated excellent linearity (r > 0.99). Rheumatoid factor, triglycerides, bilirubin, and hemoglobin did not have significant interference with the determination of tumor markers. The carry-over contamination rates were all much lower than 3%. At extremely high concentrations of AFP (277,335 ng/mL and 1,031,424 ng/mL), the measured tumor marker values were higher than the upper limit of the linear range and no hook effect occurred. The reference interval was suitable for use in clinical laboratory settings. Correlation analysis indicated a satisfactory relevance and consistency between the newly developed reagent kits and reference reagent kits, with correlation coefficients of r > 0.967 among 654 patients and healthy individuals. CONCLUSIONS: The newly developed reagent kits for tumor markers performed well in all evaluated parameters, having the potential for clinical promotion and application.

Unveiling Gambogenic Acid as a Promising Antitumor Compound: A Review.

Gambogenic acid is a derivative of gambogic acid, a polyprenylated xanthone isolated from Garcinia hanburyi. Compared with the more widely studied gambogic acid, gambogenic acid has demonstrated advantages such as a more potent antitumor effect and less systemic toxicity than gambogic acid according to early investigations. Therefore, the present review summarizes the effectiveness and mechanisms of gambogenic acid in different cancers and highlights the mechanisms of action. In addition, drug delivery systems to improve the bioavailability of gambogenic acid and its pharmacokinetic profile are included. Gambogenic acid has been applied to treat a wide range of cancers, such as lung, liver, colorectal, breast, gastric, bladder, and prostate cancers. Gambogenic acid exerts its antitumor effects as a novel class of enhancer of zeste homolog 2 inhibitors. It prevents cancer cell proliferation by inducing apoptosis, ferroptosis, and necroptosis and controlling the cell cycle as well as autophagy. Gambogenic acid also hinders tumor cell invasion and metastasis by downregulating metastasis-related proteins. Moreover, gambogenic acid increases the sensitivity of cancer cells to chemotherapy and has shown effects on multidrug resistance in malignancy. This review adds insights for the prevention and treatment of cancers using gambogenic acid.

Mapping global prevalence of menopausal symptoms among middle-aged women: a systematic review and meta-analysis.

BACKGROUND: Women at middle age are puzzled by a series of menopausal disturbances, can be distressing and considerably affect the personal, social and work lives. We aim to estimate the global prevalence of nineteen menopausal symptoms among middle-aged women by performing a systematic review and meta-analysis. METHODS: Comprehensive search was performed in multiple databases from January, 2000 to March, 2023 for relevant studies. Random-effect model with double-arcsine transformation was used for data analysis. RESULTS: A total of 321 studies comprised of 482,067 middle-aged women were included for further analysis. We found varied prevalence of menopausal symptoms, with the highest prevalence of joint and muscular discomfort (65.43%, 95% CI 62.51-68.29) and lowest of formication (20.5%, 95% CI 13.44-28.60). Notably, South America shared dramatically high prevalence in a sort of menopausal symptoms including depression and urogenital symptoms. Besides, countries with high incomes (49.72%) had a significantly lower prevalence of hot flashes than those with low (65.93%), lower-middle (54.17%), and upper-middle (54.72%, p < 0.01), while personal factors, such as menopausal stage, had an influence on most menopausal symptoms, particularly in vaginal dryness. Prevalence of vagina dryness in postmenopausal women (44.81%) was 2-fold higher than in premenopausal women (21.16%, p < 0.01). Furthermore, a remarkable distinction was observed between body mass index (BMI) and prevalence of sleep problems, depression, anxiety and urinary problems. CONCLUSION: The prevalence of menopausal symptoms affected by both social and personal factors which calls for attention from general public.

Mesenchymal stem cell-regulated miRNA-mRNA landscape in acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a major challenge in the field of hepatology. While mesenchymal stem cell (MSC) therapy can improve the prognosis of patients with ACLF, the molecular mechanisms through which MSCs attenuate ACLF remain poorly understood. We performed global miRNA and mRNA expression profiling via next-generation sequencing of liver tissues from MSC-treated ACLF mice to identify important signaling pathways and major factors implicated in ACLF alleviation by MSCs. METHODS: Carbon tetrachloride-induced ACLF mice were treated with saline or mouse bone marrow-derived MSCs. Mouse livers were subjected to miRNA and mRNA sequencing. Related signal transduction pathways were obtained through Gene Set Enrichment Analysis. Functional enrichment, protein-protein interaction, and immune infiltration analyses were performed for the differentially expressed miRNA target genes (DETs). Hub miRNA and mRNA associated with liver injury were analyzed using LASSO regression. The expression levels of hub genes were subjected to Pearson's correlation analysis and verified using RT-qPCR. The biological functions of hub genes were verified in vitro. RESULTS: The tricarboxylic acid cycle and peroxisome proliferator-activated receptor pathways were activated in the MSC-treated groups. The proportions of liver-infiltrating NK resting cells, M2 macrophages, follicular helper T cells, and other immune cells were altered after MSC treatment. The expression levels of six miRNAs and 10 transcripts correlated with the degree of liver injury. miR-27a-5p was downregulated in the mouse liver after MSC treatment, while its target gene E2f2 was upregulated. miR-27a-5p inhibited E2F2 expression, suppressed G1/S phase transition and proliferation of hepatocytes, in addition to promoting their apoptosis. CONCLUSIONS: This is the first comprehensive analysis of miRNA and mRNA expression in the liver tissue of ACLF mice after MSC treatment. The results revealed global changes in hepatic pathways and immune subpopulations. The miR-27a-5p/E2F2 axis emerged as a central regulator of the MSC-induced attenuation of ACLF. The current findings improve our understanding of the molecular mechanisms through which MSCs alleviate ACLF.

Biochemical and Transcriptome Analyses Reveal a Stronger Capacity for Photosynthate Accumulation in Low-Tillering Rice Varieties.

Moderate control of rice tillering and the development of rice varieties with large panicles are important topics for future high-yield rice breeding. Herein, we found that low-tillering rice varieties stopped tillering earlier and had a larger leaf area of the sixth leaf. Notably, at 28 days after sowing, the rice seedlings of the low-tillering group had an average single-culm above-ground biomass of 0.84 g, significantly higher than that of the multi-tillering group by 56.26%, and their NSC (non-structural carbohydrate) and starch contents in sheaths were increased by 43.34% and 97.75%, respectively. These results indicated that the low-tillering group of rice varieties had a stronger ability to store photosynthetic products in the form of starch in their sheaths, which was thus more beneficial for their large panicle development. The results of carbon and nitrogen metabolism analyses showed that the low-tillering group had a relatively strong carbon metabolism activity, which was more favorable for the accumulation of photosynthesis products and the following development of large panicles, while the multi-tillering group showed relatively strong nitrogen metabolism activity, which was more beneficial for the development and formation of new organs, such as tillers. Accordingly, in the low-tillering rice varieties, the up-regulated genes were enriched in the pathways mainly related to the synthesis of carbohydrates, while the down-regulated genes were mainly enriched in the nitrogen metabolism pathways. This study provides new insights into the mechanism of rice tillering regulation and promotes the development of new varieties with ideal plant types.